Epilepsy is one of the most common brain disorders. Antiepileptic drugs are the mainstay of therapy for most patients, but seizure control cannot be achieved in 25% of epilepsy patients and often comes at the expense of side effects, resulting in removal from therapy. Hence, there is a critical role for better understanding molecular mechanisms of epilepsy and its development. Epilepsy has a significant genetic component, but one in which the vast majority of cases are genetically complex - affecting the penetrance, severity and the form of seizures, even within a family. Because of the challenges associated with identifying genes for complex traits, almost everything that is known about the molecular basis of epilepsy comes from relatively few families that show so-called Mendelian inheritance. Laboratory mice have traditionally been used as experimental models for epilepsy, but they also can be exceptional models for gene discovery and for the study of basic mechanisms. Moreover, the common inbred mouse strains have startlingly diverse susceptibility across most experimental and spontaneous seizure measures. In combination with sensitizing mutations, the diversity in mouse strains can be used to model that seen in human families and to identify the underlying genes. In the broader research community, however, only a few inbred strains are in frequent use, tapping only a fraction of the genetic diversity in seizure susceptibility. In this program we will determine how genetic background can shape genetic seizure disorders in mice, by examining a diverse collection of inbred strains across several seizure paradigms, identifying the major genes that underlie susceptibility in some of these strains. Using selected strains, we will identify modifiers that affect the form or severity of generalized seizures that are seeded by the introduction of known mouse or human epilepsy mutations. Suppressor modifier genes in particular will provide insight into how seizures are normally regulated in nature, i.e. without side-effects, potentially leading to more effective therapies in the future. They will also serve as candidates for genetically complex human epilepsy as well. PUBLIC HEALTH RELEVANCE: Epilepsy is a major health problem affecting over 1% of the US population. 20%-30% of all epilepsy patients are refractory to drug therapy, and seizure control, for many, comes at the expense of side effects. Epilepsy has a significant genetic component. A better understanding of genetic mechanisms of epilepsy, and in particular of genes that naturally modify seizure severity and form, is expected to lead to the development of more effective therapies in the future.